This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. O-GlcNAc transferase (OGT) is a human glycosyltransferase that is responsible for all the O-GlcNAcylation of cytoplasmic and nuclear proteins. O-GlcNAcylation is a dynamic, reversible, post-translational modification of proteins on serine and threonine residues that modulates protein activity, localization, signaling, and degradation. This modification has been implicated in numerous diseases, including Diabetes, cancer, and Alzheimer's. Better knowledge of OGT and would lead to an improved understanding of the role of this modification in cellular functions and human diseases. We are trying to solve the crystal structure of OGT in order to gain a better understanding of its mechanism and cellular function, and also to develop potent, cell-permeable inhibitors of OGT to study its role in cell culture and animal models, which will help us evaluate OGT's utility as a therapeutic target. We have obtained diffracting crystals of OGT and are close to solving the structure and additional data would greatly enhance our ability to solve the structure to high resolution.